n the last century, there have been four Influenza pandemics [1–4]. Influenza (commonly known as ”the flu”) has 4 types - out of which 3 (A/B/C) infect humans [5]. Influenza A and B genomes each have 8 negative- sense, single-stranded viral RNA segments (C has a 7-segment genome) [6]. It is possible to generate viruses with 9 segments [7,8] or even 10 segments [9]. Also, laboratory experiments show that it is possible to make airborne transmission between ferrets more viable [10]. Two of these segments - glycoproteins hemagglutinin (HA) and neuraminidase on the surface of the virus - are used to subtype the virus [11]. The ability of these segments to mix and match (termed reassortment, HxNx, currently there are 129 subtypes) creates a constantly mutating virus - making it difficult to devise an effective virus [12,13]. Also, the hemagglutinin gene causes aberrant coagulation leading to a hyper-inflammatory response [14].The eradication of human flu coincides with the global explosion of bird fluThe decreased influenza activity in 2020 in different countries [15] overlaps with the ‘emergence and spread of novel H5N8, H5N5 and H5N1’ highly pathogenic avian influenza in 2020, a cause for major concern across the globe [16].H5 - the major pandemic threat - is closely related to H1It has been known for long that H5N1 remains a pandemic threat [17,18]. The first outbreak of H5N1 in humans occurred in 1997 in Hong Kong, wherein infection was confirmed in 18 people, 6 of whom died [19] - as well as another fatal incident in a child [20]. In 2004, 8 out 10 infected died in Vietnam [21] - while 12 confirmed and 21 suspected cases were retrospectively identified in Thailand [22]. Small clusters were detected in 2005 in Indonesia [23]. H5 is closely related (Fig 1) to H1 (and H2) - and distantly to H3. Its is also notable that the C-Terminal of the hemagglutinin protein is quite conserved, inspite of major variations in the other parts (Fig 1). So, that part of the protein be very critical for viral infectivity (everything changes, but it does not), and thus might be a good target for drugs, or antibodies.H7N9 is another potential zoonotic threatIn 2013, 111 Cases of H7N9 infection was quite fatal (‘76.6% were admitted to an intensive care unit (ICU), and 27.0% died’) [24]. H7N9 samples were also collected from 25 March 2014 to 31 March 2016 at the First Affiliated Hospital, College of Medicine of Zhejiang University, Hangzhou, China [25]. Moderna has also started mRNA vaccine trials for H7N9 [26].Are flu tests missing out on the circulating strain?Biofire FilmArray (one of the few methods used to detect flu [27]) checks only 2 strains (H1N1/H3N2). There are huge variation in the flu genome (say between H1 and H3). Even within the same type there is a lot of vari- ation. For example, A/Perth/267/2009 (used in the Biofire) is only 74% similar to 7A/swine/China/Guangdong- ZSBS/2017 (Fig 2). It is known that a relatively smaller change breaks the SARS-Cov2 PCR test [28], so such variation can easily render the flu test inaccurate. Metagenomic studies will help identify the circulating strain - or rule out the hypothesis presented in this paper. If it is the flu, a specific therapy (like Tamiflu) may help bring down mortality - and flu shots can also be modified to reflect the circulating strain.H
Assessing different interventions against Avian Influenza A (H7N9) infection by an epidemiological model